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      Seminal fluid and the generation of regulatory T cells for embryo implantation.

      American Journal of Reproductive Immunology

      Abortion, Spontaneous, immunology, Animals, Dendritic Cells, Embryo Implantation, Endometrium, Female, Humans, Infertility, Isoantigens, Male, Mice, Pre-Eclampsia, Pregnancy, Pregnancy Complications, Prostaglandins E, Semen, Seminal Plasma Proteins, T-Lymphocytes, Regulatory, Transforming Growth Factor beta

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          Abstract

          T regulatory (Treg) cells are essential mediators of the maternal immune adaptation necessary for embryo implantation. In mice, insufficient Treg cell activity results in implantation failure, or constrains placental function and fetal growth. In women, Treg cell deficiency is linked with unexplained infertility, miscarriage, and pre-eclampsia. To devise strategies to improve Treg cell function, it is essential to define the origin of the Treg cells in gestational tissues, and the regulators that control their functional competence and recruitment. Male seminal fluid is a potent source of the Treg cell-inducing agents TGFβ and prostaglandin E, and coitus is one key factor involved in expanding the pool of inducible Treg cells that react with paternal alloantigens shared by conceptus tissues. In mice, coitus initiates a sequence of events whereby female dendritic cells cross-present seminal fluid antigens and activate T cells, which in turn circulate via the blood to be sequestered into the endometrium. Similar events may occur in the human genital tract, where seminal fluid induces immune cell changes that appear competent to prime Treg cells. Improved understanding of how seminal fluid influences Treg cells in women should ultimately assist in the development of new therapies for immune-mediated pathologies of pregnancy. © 2013 John Wiley & Sons A/S.

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          Most cited references 87

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          Regulatory T cells and Foxp3.

          Regulatory T (Treg) cells play central role in regulation of immune responses to self-antigens, allergens, and commensal microbiota as well as immune responses to infectious agents and tumors. Transcriptional factor Foxp3 serves as a lineage specification factor of Treg cells. Paucity of Treg cells due to loss-of-function mutations of the Foxp3 gene is responsible for highly aggressive, fatal, systemic immune-mediated inflammatory lesions in mice and humans. Recent studies of Foxp3 expression and function provided critical novel insights into biology of Treg cells and into cellular mechanisms of the immune homeostasis. © 2011 John Wiley & Sons A/S.
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            Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4+CD25+ regulatory T cell proliferation

            The mechanisms through which regulatory T cells accumulate in lymphoid organs of tumor-bearing hosts remain elusive. Our experiments indicate that the accumulation of CD4 + CD25 + regulatory T cells (T reg cells) expressing FoxP3 and exhibiting immunosuppressive function originates from the proliferation of naturally occurring CD25 + T cells and requires signaling through transforming growth factor (TGF)–β receptor II. During tumor progression, a subset of dendritic cells (DCs) exhibiting a myeloid immature phenotype is recruited to draining lymph nodes. This DC subset selectively promotes the proliferation of T reg cells in a TGF-β–dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-β and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.
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              Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict.

              Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                23480148
                10.1111/aji.12107

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